Breast cancer is a complex and heterogeneous disease. Early detection of breast cancer improves the chances of successful treatment and recovery. Routine screening mammography has increased the detection of Stage I breast cancers and correspondingly, many more women are being diagnosed with lymph node-negative tumors. (B. Cady, 1997, Surg Oncol Clin N Am 6:195-202). About 43% of the approximately 240,000 women in the United States diagnosed with breast cancer each year are node-negative.
Based on the current guidelines, 85-90% of node-negative patients are candidates for systemic adjuvant therapy after surgery. Such systemic adjuvant therapy may include chemotherapy and hormonal therapy. However, about 60-70% of women with node-negative breast cancer who receive local treatment (mastectomy or lumpectomy and radiation) will not experience distant recurrence. Treatment decisions for breast cancer patients benefit from the assessment of each patient's risk for metastasis and response to treatment using multiple clinical and histopathological parameters.
Several recent studies have used microarrays to demonstrate that a patient's gene expression profile can also provide useful prognostic information. A subset of these studies has received focused attention due to their size, and the extent of their validation. (L J van't Veer, H. Dai et al., 2002, Nature 415:530-536; M J van de Vijver, Y D He et al., 2002, N Engl J Med 347:1999-2009; Y. Wang, J G Klijn et al., 2005, Lancet 365:671-679; H. Dai, L J van't Veer et al., 2005, Cancer Res 15:4059-4066; and H Y Chang, D S Nuyten et al., 2005, Proc Natl Acad Sci USA 102:3738-3743).
The resulting confidence garnered for the 70-gene prognostic signature identified by van't Veer, Dai et al. (2002, Nature 415:530-536) has led to its incorporation into a European trial, the Microarray for Node-Negative Disease May Avoid Chemotherapy (MINDACT). Likewise, the PCR-based, 21-gene predictive signature described by S P Paik, S. Shak et al (2004, N Engl J Med 351:2817-2826) has been included in a phase III trial by The Breast Cancer Intergroup of North America (Program for the Assessment of Clinical Cancer Tests (PACCT). (V G Kaklamani and W J Gradishar, 2006, Curr Treat Options Oncol 7:123-8).
The 21-gene predictive signature (including 5 normalization genes) by SP Paik (2004, N Engl J Med 351:2817-2826) was derived from Tamoxifen-treated patients. The independence of that signature has drawn concern due to its substantial overlap with genes and/or proteins already used in conventional immunohistochemistry (IHC) tests. (D R Carrizosa and L A Carey, 2005, The American Journal of Oncology Review 4:7-10). The standard hormonal therapy for ER-positive breast cancer patients is changing from Tamoxifen alone, to sequential use of Tamoxifen plus aromatase inhibitors, or aromatase inhibitors alone. (E P Winer, C. Hudis et al., 2005, J Clin Oncol 23: 619-629; S M Swain, 2005, N Engl J Med 353:2807-9). A prognostic tool that is independent of Tamoxifen treatment can be important in providing a measure of the baseline risk for patients who plan on taking aromatase inhibitors.
Thus, there is a need for a gene-based prognostic assay that can be used for routine clinical laboratory testing in predicting the risk of distant metastasis in breast cancer patients. Ideally, the assay would require the measurement of expression levels of a relatively small number of genes, and the mRNA encoded by such genes can be readily obtained from tumor tissues preserved by routine collection methods such as FFPE tumor sections. Information of the risk for distant metastasis can be used in guiding treatment strategies for breast cancer patients, particularly early stage lymph node-negative patients, such that patients who are at higher risk of distant metastasis are treated properly, and patients who are at lower risk of distant metastasis may be spared the side effects of certain treatments.